A surgeons review of adjuvant chemotherapy

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A surgeons review of adjuvant chemotherapy

• ESMO International Symposium
• On Chest Tumors
• Geneva, March 30 2007
• Eric Vallières MD FRCSC
• Swedish Cancer Institute
• Seattle, WA

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Clinical IB, IIA, IIB diseases

• Resection by lobectomy or more if cardiopulmonary
  reserves OK
• 5-y Survival 40-60

cT2N0 LUL NSCLC
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Clinical IB, IIA, IIB diseases
OR 5-y mortality 60-40
systemic recurrence
Hence the need/ role for additional help ?
cT2N0 RUL NSCLC
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OUTLINE

• The data 2007
• Some thoughts ( no data)
• Notes of caution
• The future

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OUTLINE

• The data 2007
• Some thoughts ( no data)
• Notes of caution
• The future

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Meta-analysis 1995
IALT ASCO 2003
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ASCO 2004

• CALGB 9633

NCIC BR 10
Chemotherapy
Chemotherapy
Observation
Observation
71 59
69 54
HR 0.62 p0.028
HR 0.7 p0.012
YRS
5yrs
4yrs
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Adjuvant chemotherapy
Within 40 days postop
NCIC, SWOG, ECOG, CALGB
Winton TL et al, NEJM 352(25) 2589-97, 2005
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JBR.10 - Survival
Winton TL et al, NEJM 352(25) 2589-97, 2005
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Adjuvant chemotherapy
Within 28 to 56 days postop
Strauss GM et al, PASCO 2004, 23 7019
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ASCO 2006 (137/155 of total events) ABSTR
7007CALGB 9633 - OVERALL SURVIVAL
1.0
Observation
Chemo
0.8
0.6
Probability
0.4
0.2
0.0
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
Survival Time (Years)
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Updated CALGB 9633 Conclusions

• In final analysis the trend persisted,
• but the significance was lost
• (HR 0.8, p 0.1)
• Subset analysis suggests a role in T2N0 gt 4 cm in
  size
• Emphasizes risks with early termination/
  reporting
• Negative trial? Or Underpowered Trial?
• Cisplatin vs. Carboplatin?

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ASCO 2005 ANITA OS
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ANITA Overall survival
OBS. NVB CDDP Median months 43.8 65.8 1-year
survival 3.1 80.4 83.5 2-year survival
5.1 62.8 67.9 5-year survival
8.6 42.6 51.2 7-year survival
8.4 36.8 45.2
logrank p value 0.013
Douillard JY et al, Lancet Oncol 2006 7 719-27
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Douillard JY et al, Lancet Oncol 2006 7 719-27
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N0
N1
N2
Douillard JY et al, Lancet Oncol 2006 7 719-27
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Lung adjuvant cisplatin evaluation (LACE)Pignon
et al, ASCO 2006

• Individual patient data from cisplatin based
  adjuvant studies ALPI, ANITA, BLT, IALT, JBR10
• 5 trials including 4,584 patients
• Median follow-up 5.1 years (3.1 5.9)

Pignon JP et al, J Clin Oncol 2006, 24(18S) 366S
abstract 7008
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Results - LACE

• Overall HR (death) 0.89 (CI 0.82-0.96, p lt0.005)
• HR (death) by stage
• IA 1.41 (CI 0.96- 2.09
• IB 0.93 (CI 0.78-1.10)
• II 0.83 (CI 0.73-0.95)
• III 0.83 (CI 0.73-0.95)

Pignon JP et al, J Clin Oncol 2006, 24(18S) 366S
abstract 7008
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Adjuvant platinum chemo -Subset Analysis -
StageJoan Schiller ASCO 2006 Discussion
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Post-operative chemotherapy is the new
standard of care for good PS pts after R0
anatomic resectionp stages IIA-B, IIIA NSCLC,
and maybe larger IBs
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OUTLINE

• The data 2005
• Some thoughts ( no data)
• Notes of caution
• The future

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Every one ?

• Clinical trial population
• Good PS
• Br10 9633 median age 61,
• IALT ANITA lt 75 y
• Older crowd ? Well selected possibly
• Co-morbidities ? Beware not studied medical
  oncologist should make that call...

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Incidental p IIIA N2 R0 ?

• Not included in North American trials, but was
  the best subset in IALT...
• Benefits seen in ANITA (and LACE) as well

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IALT Interaction with p stage
Hazard ratio
Stage I
p0.41
Stage II
Stage III
Total effect
0.86
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Incidental p IIIA N2 R0 ?

Adjuvant chemo YES There may be a role for
adjuvant radiotherapy in this era of adjuvant C.
(ANITA) If RT, concurrent or sequential RTx
?If concurrent more toxic and may come at cost
of systemic treatment ( ECOG 3590)
Bonner JA, JCO 24(19)2978-9, 2006
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OUTLINE

• The data 2005
• Some thoughts ( no data)
• Notes of caution
• The future

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Adjuvant Chemotherapy/ Intraop staging

• It is now even more imperative that we better
  node stage our patients intra-op as the results
  may now alter the pts recommended adjuvant
  treatment.
• The absence/ paucity of regional lymph nodes in
  the pathology specimen is definitely sub-par
  lung cancer surgery...

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Adjuvant Chemotherapy / Compliance

• Over the last 25 years, on trial, the delivery of
  the intended adjuvant chemotherapy has been
  difficult
• LCSG 801 (CAP 4) 53
• JCOG 8601 (C Vd 3) 68
• ALPI (MVdP 3) 70
• BLT (cisP X 3) 64
  got all 3
• IALT (cisP X 2-4) 74 at
  least 240 mg/ m²

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Adjuvant C compliance off trial

• Single academic center Toronto,
• review of all R0 stages pI-IIIa in 2 years
• 5/2003-5/2004 (post IALT) 36/ 115 referred (31)
• 6/2004-5/2005 (post Br.10, CALGB) 56/89 referred
  (63)

Kassam F et al J Thor Oncology 2007, 2(1) 39-43
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27 Or 50 of those that did not get C
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Kassam F et al J Thor Oncology 2007, 2(1) 39-43
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OUTLINE

• The data 2005
• Some thoughts ( no data)
• Notes of caution
• The future

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The future Better staging than TNM ?
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Selecting Patients for Adjuvant Therapy

• Not every patient is at risk of recurrence after
  R0 resections
• Can we identify the patients that do not need
  adjuvant chemotherapy and avoid over-treatment ?
• Can we identify those that should definitely
  receive adjuvant treatment and avoid
  under-treatment?

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GENOMICS
Potti et al NEJM 355 570-80, 2006
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Proteomics
N41
N25
Cluster analysis based on Prognosis ID 15
distinct Protein Peaks under Investigation (13/15
novel markers so far)
Yanagiasawa Lancet 2003
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Combining genomics and proteomics ?
RNA Expression Array
MALDI-MS Proteomic Array
Gene expression profile
Harpole, pers. comm.
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Selecting the right Adjuvant Therapy for those
who need it

• Individualizing the cytotoxic chemotherapy ?
• Individualizing the dose ? ( smokers vs. non
  smokers...)
• Targeted therapies /- cytotoxics

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Kaplan-Meier Survival Curves by ERCC1 status
Olaussen et al NEJM 355 983-91, 2006
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Kaplan-Meier Survival Curves by ERCC1 status
Olaussen KA et al. N Engl J Med 2006355983-991
Olaussen et al NEJM 355 983-91, 2006
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RRM1 as a predictor of response to Gemcitabine
chemotherapy ?
Bepler et al J Clin Oncol 2006 244731-37
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Conclusions

• Post-operative chemotherapy is the new standard
  of care for stage II and III good PS pts after R0
  anatomic resection
• but it may be a hard game to play
• the future of adjuvant therapy is for better
  staging and individualizing therapy

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THANK YOU